<i>Dlx5</i>and<i>Dlx6</i>Regulate the Development of Parvalbumin-Expressing Cortical Interneurons

Wang, Yanling; Dye, Catherine A.; Sohal, Vikaas S.; Long, Jason E.; Estrada, Rosanne C.; Roztocil, Tomas; Lufkin, Thomas; Deisseroth, Karl; Baraban, Scott C.; Rubenstein, John L.R.

doi:10.1523/jneurosci.5963-09.2010

Cited by 172 publications

(150 citation statements)

References 62 publications

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“…These data for GAD67 are in agreement with a previous study with the same promoter in an AAV (Teschemacher et al, 2005). Finally, in the case of the Dlx5/6 promoter, the reporter gene was expressed at a very high level but in a very small subset of cells, probably GABAergic interneurons (Cobos et al, 2005;Potter et al, 2009;Wang et al, 2010). The homeodomain transcription factors encoded by distal-less homeobox 5 and 6 are transcribed convergently and the mRNAs are detected in virtually all GABAergic neurons of the brain.…”

Section: Discussionsupporting

confidence: 90%

“…3C-E). This is consistent with published findings that Dlx genes are expressed in GABAergic interneurons of the brain (Cobos et al, 2005;Potter et al, 2009;Wang et al, 2010), and that there is sparse expression of Drd1a in pyramidal cells throughout the CA1, 2, 3 fields and dentate granular cells in the anterior of the dorsal hippocampus (Fremeau et al, 1991). The mean fluorescence intensity per cell for the PGK and GAD67 promoters in the hippocampus were very similar to those in the striatum (Fig.…”

Section: Transduction Efficiency and Transcriptional Activity Of The supporting

confidence: 91%

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Restricted Transgene Expression in the Brain with Cell-Type Specific Neuronal Promoters

Delzor

Dufour

Petit

et al. 2012

Human Gene Therapy Methods

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Tissue-targeted expression is of major interest for studying the contribution of cellular subpopulations to neurodegenerative diseases. However, in vivo methods to investigate this issue are limited. Here, we report an analysis of the cell specificity of expression of fluorescent reporter genes driven by six neuronal promoters, with the ubiquitous phosphoglycerate kinase 1 (PGK) promoter used as a reference. Quantitative analysis of AcGFPnuc expression in the striatum and hippocampus of rodents showed that all lentiviral vectors (LV) exhibited a neuronal tropism; however, there was substantial diversity of transcriptional activity and cell-type specificity of expression. The promoters with the highest activity were those of the 67 kDa glutamic acid decarboxylase (GAD67), homeobox Dlx5/6, glutamate receptor 1 (GluR1), and preprotachykinin 1 (Tac1) genes. Neuron-specific enolase (NSE) and dopaminergic receptor 1 (Drd1a) promoters showed weak activity, but the integration of an amplification system into the LV overcame this limitation. In the striatum, the expression profiles of Tac1 and Drd1a were not limited to the striatonigral pathway, whereas in the hippocampus, Drd1a and Dlx5/6 showed the expected restricted pattern of expression. Regulation of the Dlx5/6 promoter was observed in a disease condition, whereas Tac1 activity was unaffected. These vectors provide safe tools that are more selective than others available, for the administration of therapeutic molecules in the central nervous system (CNS). Nevertheless, additional characterization of regulatory elements in neuronal promoters is still required.

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Section: Discussionsupporting

confidence: 90%

Section: Transduction Efficiency and Transcriptional Activity Of The supporting

confidence: 91%

Restricted Transgene Expression in the Brain with Cell-Type Specific Neuronal Promoters

Delzor

Dufour

Petit

et al. 2012

Human Gene Therapy Methods

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“…Cluster 2 was defined by GO terms related to interneuron differentiation, cell morphogenesis and forebrain development, suggesting that this cluster contains interneuron precursors that have left the cell cycle and become postmitotic. These precursor cells turn on expression of selector and terminal differentiation genes that allow fate specific functions, including homeobox transcription factors such as aristaless homeobox gene (Arx), LIM/homeobox protein 6 (Lhx6) and drosophila distalless gene 1 and 5 (Dlx1/5), all known to be crucial for GABAergic interneuron differentiation [22][23][24][25][26]. Cluster 3 was characterized by genes associated with neuron differentiation, but also incorporated genes controlling migration and neuronal projection, including plexinA2 (Plxna2) and kinesin family member 5A (Kif5a).…”

Section: Resultsmentioning

confidence: 99%

Topographical transcriptome mapping of the mouse medial ganglionic eminence by spatially-resolved RNA-seq

Zechel¹,

Zając²,

Lönnerberg³

et al. 2014

Genome Biol

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Background: Cortical interneurons originating from the medial ganglionic eminence, MGE, are among the most diverse cells within the CNS. Different pools of proliferating progenitor cells are thought to exist in the ventricular zone of the MGE, but whether the underlying subventricular and mantle regions of the MGE are spatially patterned has not yet been addressed. Here, we combined laser-capture microdissection and multiplex RNA-sequencing to map the transcriptome of MGE cells at a spatial resolution of 50 μm. Results: Distinct groups of progenitor cells showing different stages of interneuron maturation are identified and topographically mapped based on their genome-wide transcriptional pattern. Although proliferating potential decreased rather abruptly outside the ventricular zone, a ventro-lateral gradient of increasing migratory capacity was identified, revealing heterogeneous cell populations within this neurogenic structure.

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“…In mice, the brain of Dlx1-null mutants displays no overt phenotype at birth, but later in life they develop epileptic seizures (Cobos et al, 2005). Dlx5/6 +/-mice, the cortex of which appears normal, have spontaneous electrographic seizures and reduced power of gamma oscillations suggesting defects in cortical interneurons; in addition, there is evidence for defective development of PVexpressing interneurons in Dlx5/6 -/-and Dlx5 -/-mutants (Wang et al, 2010). Thus, Dlx proteins could adopt a specific role in the adult brain or subtle alterations that occur during development could have delayed consequences.…”

Section: Research Articlementioning

confidence: 99%

An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain

Poitras

Lesage-Pelletier

et al. 2010

Development

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SUMMARYDlx homeobox genes play a crucial role in the migration and differentiation of the subpallial precursor cells that give rise to various subtypes of -aminobutyric acid (GABA)-expressing neurons of the forebrain, including local-circuit cortical interneurons. Aberrant development of GABAergic interneurons has been linked to several neurodevelopmental disorders, including epilepsy, schizophrenia, Rett syndrome and autism. Here, we report in mice that a single-nucleotide polymorphism (SNP) found in an autistic proband falls within a functional protein binding site in an ultraconserved cis-regulatory element. This element, I56i, is involved in regulating Dlx5/Dlx6 homeobox gene expression in the developing forebrain. We show that the SNP results in reduced I56i activity, predominantly in the medial and caudal ganglionic eminences and in streams of neurons tangentially migrating to the cortex. Reduced activity is also observed in GABAergic interneurons of the adult somatosensory cortex. The SNP affects the affinity of Dlx proteins for their binding site in vitro and reduces the transcriptional activation of the enhancer by Dlx proteins. Affinity purification using I56i sequences led to the identification of a novel regulator of Dlx gene expression, general transcription factor 2 I (Gtf2i), which is among the genes most often deleted in Williams-Beuren syndrome, a neurodevelopmental disorder. This study illustrates the clear functional consequences of a single nucleotide variation in an ultraconserved non-coding sequence in the context of developmental abnormalities associated with disease.

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Dlx5andDlx6Regulate the Development of Parvalbumin-Expressing Cortical Interneurons

Cited by 172 publications

References 62 publications

Restricted Transgene Expression in the Brain with Cell-Type Specific Neuronal Promoters

Restricted Transgene Expression in the Brain with Cell-Type Specific Neuronal Promoters

Topographical transcriptome mapping of the mouse medial ganglionic eminence by spatially-resolved RNA-seq

An SNP in an ultraconserved regulatory element affects Dlx5/Dlx6 regulation in the forebrain

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